(Re)Writing Communities and Identities

(Re)Writing Communities and Identities enables college-level students to develop their ability to compose various informative and expressive genres, including analyses, reflections, summaries, syntheses, and informative reports. While students raise their consciousness about their writing process and audience-based informative strategies, they also familiarize themselves with important social and cultural issues related to the theme of identities and communities.https://newprairiepress.org/ebooks/1041/thumbnail.jp

Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial

Background Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. Methods RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. Findings Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61–69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1–10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688–1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4–82·5) in the no ADT group and 80·4% (76·6–83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. Interpretation Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population

Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial

Background Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. Methods RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov , NCT00541047 . Findings Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60–69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0–10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612–0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6–75·7) in the short-course ADT group and 78·1% (74·2–81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. Interpretation Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. Funding Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

A Survey Of Putative Anxiety-associated Genes In Panic Disorder Patients With And Without Bladder Symptoms

Background We have previously described a subtype of panic disorder (PD) that we termed ‘bladder syndrome’, characterized by urological and bladder symptoms (and possibly interstitial cystitis) in the patients and/or their family members and confirmed the validity of this subset in family linkage and association analysis. In this study, we determine (a) whether 20 single-nucleotide polymorphisms (SNPs) reported in the literature can be replicated in a new PD dataset and (b) whether dividing the sample into those with and without the ‘bladder syndrome’ can help to resolve the genetic heterogeneity within this new sample. Methods We selected 20 putative associated SNPs from the literature, taken from studies published since 2004. We tested these SNPs for association in a sample of 351 PD patients and 552 controls, and then divided them into subgroups of 92 patients from bladder families and 259 from nonbladder families. Results (a) When analyzed in all PD patients, none of the 20 SNPs appeared to be replicated (except for SLC6A4 from our previous study, but in a sample that overlaps substantially with that in our previous report). (b) However, some intriguing findings emerged when we separated bladder from nonbladder families: SLC6A4, reported by us previously, yielded stronger evidence than before (P=0.0018) when examined only in nonbladder families, and in contrast, is not statistically significant in bladder families. Two other markers yielded nominally significant results in bladder families – rs5751876 in ADORA2A (P=0.046) and rs12579350 in TMEM16B (P=0.035) – but were not significant in nonbladder families. (c) Two markers had noticeably lower P-values when we differentiated the women and analyzed them separately – rs12579350 in TMEM16B (P-value decreased from 0.035, as above, to 0.00055) and a different SNP in ADORA2A, rs4822492 (P-value decreases from 0.07 to 0.028). Significance Our results indicate that most of the 20 reported associations do not hold up when PD is analyzed as one group. However, our findings provide further evidence that PD with bladder symptoms may be genetically different from PD without bladder. We suggest that it is worth pursuing SLC6A4 in nonbladder PD, and ADORA2A and TMEM16B in bladder PD. Also, the possibility of a male–female difference in PD is worth pursuing. We also briefly discuss issues of replication and multiple tests

Cationic Copper(II) Porphyrins Intercalate into Domains of Double-Stranded RNA

A cationic, copper­(II)-containing ligand, derived from bulky 5,10,15,20-tetrakis­(<i>N</i>-methylpyridinium-4-yl)­porphyrin, Cu­(T4), and two sterically friendlier forms, [<i>trans</i>-5,15-di­(<i>N</i>-methylpyridinium-4-yl)­porphyrinato]­copper­(II), Cu­(<i>t</i>D4), and [<i>cis</i>-5,10-di­(<i>N</i>-methylpyridinium-4-yl)­porphyrinato]­copper­(II), Cu­(<i>c</i>D4), bind to DNA and RNA hosts. Six hairpin-forming RNA 18-mer sequences and two previously studied DNA analogues serve as convenient binding platforms of programmable base composition. A crystal structure shows that the copper center of Cu­(<i>t</i>D4) is four-coordinate, establishing compatibility with intercalative binding as well as susceptibility to solvent-induced emission quenching. From the hypochromic responses and the induced emission intensities obtained with all three porphyrins, it is clear that internalization into the RNA host occurs, irrespective of the base pair composition. Further analysis reveals that the porphyrins intercalate into the double-stranded stem domains. Subtle geometric and/or electronic aspects of the binding account for the signs of induced circular dichroic signals and splitting of the Soret band of Cu­(<i>t</i>D4)

Cationic Copper(II) Porphyrins Intercalate into Domains of Double-Stranded RNA

A cationic, copper­(II)-containing ligand, derived from bulky 5,10,15,20-tetrakis­(<i>N</i>-methylpyridinium-4-yl)­porphyrin, Cu­(T4), and two sterically friendlier forms, [<i>trans</i>-5,15-di­(<i>N</i>-methylpyridinium-4-yl)­porphyrinato]­copper­(II), Cu­(<i>t</i>D4), and [<i>cis</i>-5,10-di­(<i>N</i>-methylpyridinium-4-yl)­porphyrinato]­copper­(II), Cu­(<i>c</i>D4), bind to DNA and RNA hosts. Six hairpin-forming RNA 18-mer sequences and two previously studied DNA analogues serve as convenient binding platforms of programmable base composition. A crystal structure shows that the copper center of Cu­(<i>t</i>D4) is four-coordinate, establishing compatibility with intercalative binding as well as susceptibility to solvent-induced emission quenching. From the hypochromic responses and the induced emission intensities obtained with all three porphyrins, it is clear that internalization into the RNA host occurs, irrespective of the base pair composition. Further analysis reveals that the porphyrins intercalate into the double-stranded stem domains. Subtle geometric and/or electronic aspects of the binding account for the signs of induced circular dichroic signals and splitting of the Soret band of Cu­(<i>t</i>D4)

Pathogenesis of a novel porcine parainfluenza virus type 1 isolate in conventional and colostrum deprived/caesarean derived pigs

Two experimental challenge studies were conducted to evaluate the pathogenesis of a porcine parainfluenza virus type 1 (PPIV-1) isolate. Four-week-old conventional (CON) pigs were challenged in Study 1 and six-week-old caesarean derived/colostrum deprived (CDCD) pigs were challenged in Study 2. Results indicate that PPIV-1 shedding and replication occur in the upper and lower respiratory tracts of CON and CDCD pigs as detected by RT-qPCR and immunohistochemistry. Mild macroscopic lung lesions were observed in CON pigs but not in CDCD pigs. Microscopic lung lesions were mild and consisted of peribronchiolar lymphocytic cuffing and epithelial proliferation in CON and CDCD pigs. Serum neutralizing antibodies were detected in the CON and CDCD pigs by 14 and 7 days post inoculation, respectively. This study provides evidence that in spite of PPIV-1 infection and replication in challenged swine, significant clinical respiratory disease was not observed.This article is published as Welch, Michael, Jie Park, Karen Harmon, Jianqiang Zhang, Pablo Piñeyro, Luis Giménez-Lirola, Min Zhang, Chong Wang, Abby Patterson, and Phillip C. Gauger. "Pathogenesis of a novel porcine parainfluenza virus type 1 isolate in conventional and colostrum deprived/caesarean derived pigs." Virology 563 (2021): 88-97. DOI: 10.1016/j.virol.2021.08.015. Copyright 2021 The Authors. Attribution 4.0 International (CC BY 4.0). Posted with permission

Spatially revealed roles for lncRNAs in Drosophila spermatogenesis, Y chromosome function and evolution

Abstract Unlike coding genes, the number of lncRNA genes in organism genomes is relatively proportional to organism complexity. From plants to humans, the tissues with highest numbers and levels of lncRNA gene expression are the male reproductive organs. To learn why, we initiated a genome-wide analysis of Drosophila lncRNA spatial expression patterns in these tissues. The numbers of genes and levels of expression observed greatly exceed those previously reported, due largely to a preponderance of non-polyadenylated transcripts. In stark contrast to coding genes, the highest numbers of lncRNAs expressed are in post-meiotic spermatids. Correlations between expression levels, localization and previously performed genetic analyses indicate high levels of function and requirement. More focused analyses indicate that lncRNAs play major roles in evolution by controlling transposable element activities, Y chromosome gene expression and sperm construction. A new type of lncRNA-based particle found in seminal fluid may also contribute to reproductive outcomes